Angiotensin II (AII) is an octapeptide hormone which is a component of the renin-angiotensin system. In addition to being a circulating hormone which affects the cardiovascular system, the adrenal cortex, the peripheral autonomic nervous system, and the kidneys, AII is also known to affect the central nervous system. AII is now believed to act as a neuropeptide in the central nervous system (CNS) and may modulate the release and subsequent action of other neurotransmitters (Unger et al. (1988) Circulation 77 (Suppl I): 40-54).
Specific high affinity receptors for AII have been identified and localized in different regions of the CNS (Mann (1982) Exp. Brain Res. 4 (Suppl): 242). Stimulation of AII receptors in the CNS elicits a complex, but highly reproducible and concerted pattern of behavioral, cardiovascular, and endocrine responses (Fritzsimons (1980) Rev. Physiol. Biochem. Pharmacol. 87:117). These include CNS-induced elevation of blood pressure, increased drinking and sodium appetite, and release of antidiuretic hormone, oxytocin, luteinizing hormone, and prolactin (Scholken et al. (1982) Experientia 38:469). The CNS effects of AII could lead to hypertension and other cardiovascular diseases through inhibition of the baroreceptor reflex, increase in salt consumption, volume expansion, and increased peripheral resistance. Besides the cardiovascular system, AII may also influence the reproductive system and other brain functions, such as memory (Koller et al. (1975) Neuroscience Lett. 14: 71-75).
The major functions of AII in the CNS can be classified into three groups which may share, at least in part, overlapping mechanisms of action. The first major function of AII in the CNS is regulation of body fluid volume in response to hypovolemia, involving, for example, regulation of thirst, blood pressure increases, vasopressin release, sodium appetite increase, adrenocorticotropic hormone (ACTH) release, and aldosterone release (Unger et al. (1988) Circulation 77 (Suppl I): 40-54, and references cited therein). This CNS function of AII is closely related to the peripheral role of AII in hypertension.
A second function of AII in the CNS, although less well defined, is the regulation of gonadotrophic hormone releasing hormones and pituitary hormones during the reproductive cycle and pregnancy (Unger et al., supra).
A third possible CNS function of AII is a synaptic function. AII appears to interact with neurotransmitters such as acetylcholine (ACh), catecholamines, serotonin, and other neuroactive peptides (Unger et al., supra). Although the amount of data supporting this CNS function of AII is limited, published results suggest that increased AII activity in the brain exerts an inhibitory effect on cholinergic neurons resulting in impaired cognitive performance. Therefore, compounds that inhibit AII biosynthesis, or block AII receptor activation may enhance cognition.
The role of peptides in learning and memory was initially investigated by D. DeWied in the late 1960's and early 1970's. This led Morgan and Routtenberg (Science (1977) 196: 87-89) to investigate the role of AII in mediating retention of a passive avoidance (PA) response in rats. These authors demonstrated that rats injected with AII into the dorsal neostriatum, a brain area that has a high concentration of AII as well as precursors and metabolic enzymes for AII biosynthesis, showed a disruption in retention of a PA response. The authors demonstrated specificity of the response in terms of both the location in the brain, and the peptide used (unlike AII, thyrotropin releasing hormone or lysine-8-vasopressin had no effect). This study showed that increased AII in the dorsal neostriatum results in a cognitive impairment which is most likely related to AII modulation of neuronal activity that is necessary for consolidation of newly acquired information.
A different approach for investigating the behavioral effects of AII in the CNS was taken by Koller et al. (Neuroscience Letters(1975) 14: 71-75). These authors injected renin into the lateral ventricle of the brain (IVT) and measured increases in AII in cerebrospinal fluid (CSF); AII levels increased from 40 to about 5000 fmol per mL. This increase in AII was accompanied by a disruption of avoidance learning. These results suggested that renin-stimulated biosynthesis of AII could disrupt memory. Administration into the IVT of the angiotensin-converting enzyme (ACE) inhibitor SQ 14225 (captopril) prior to the renin injection, prevented the renin-induced avoidance disruption. Applicants have also found that renin administered IVT produces a dose-related amnesia in a PA task, which is prevented by IVT administration of the ACE inhibitor captopril. These results suggest that increased AII levels in the brain lead to a disruption of learned avoidance. This amnesia can be achieved by direct administration into a discrete brain area of either AII or renin, an enzyme involved in endogenous AII biosynthesis.
In the literature on the neuropathology and neurochemistry of Alzheimer's disease (AD), there are two reports of altered levels of dipeptidyl carboxypeptidase (angiotensin-converting enzyme, ACE) in human CSF and brain tissue. Arrequi et al. (J. Neurochemistry(1982) 38: 1490-1492) found increased ACE activity in the hippocampus, parahippocampal gyrus, frontal cortex, and caudate nucleus in AD patients. Zubenko et al. (Biol. Psych.21: 1365-1385 (1986) found a correlation between levels of ACE in the CSF and the severity of AD. Whether the alterations in ACE cause the progression of dementia or are correlates of the disease progress remains unknown.
Recent evidence that inhibition of ACE can have a modulatory effect on learning and memory was reported by Usinger et al. (Drug Dev. Research 14: 315-324 (1988); also European Patent application, EP 307,872 to Hoechst, published Mar. 22, 1989).
Similar results were reported by Costall et al. (Pharmacol. Biochem. Behav. 33: 573-579 (1989)) using the ACE inhibitor captopril. These authors demonstrated that subchronic treatment with captopril increased the rate of acquisition of light/dark habituation performance. Further, anticholinergic scopolamine-induced disruption of performance in this test model was prevented by daily treatment with captopril.
The ACE inhibitor SQ 29852 has also been reported to provide protective effects on memory of
(3) R.sup.3 is PA1 (a) H, PA1 (b) halo, PA1 (c) C.sub.1 -C.sub.6 alkyl, or C.sub.3 -C.sub.6 alkenyl or alkynyl, PA1 (d) R.sup.14 -(CH.sub.2).sub.x -wherein x is one, two, three, four or five, and R.sup.14 is C.sub.3 -C.sub.8 cycloalkyl, naphthyl, heteroaryl, phenyl unsubstituted or substituted with from one through five, preferably one through three, substituents comprising C.sub.1 -C.sub.4 alkyl, halo, trifluoromethyl, hydroxy, C.sub.1 -C.sub.4 alkoxy, lower acyloxy, amino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, nitro or -NHCOR.sup.10 wherein R.sup.10 is lower alkyl, phenyl unsubstituted or substituted with lower alkyl, or -NHR.sup.11 ; wherein R.sup.11 is H or C.sub.1 -C.sub.4 alkyl, PA1 (e) ##STR3## wherein R.sup.14 is independently as defined above, or (f) R.sup.14 -CH(OH)- wherein R.sup.14 is independently as defined above; PA1 (a) --(CH.sub.2).sub.x OR.sup.7 wherein R.sup.7 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 acyl, C.sub.3 -C.sub.6 cycloalkyl, phenyl, or benzyl, PA1 (b) --(CH.sub.2).sub.x NR.sup.7 R.sup.8 wherein R.sup.7 is independently as defined above and R.sup.8 is H, C.sub.1 -C4 alkyl, phenyl, benzyl, or C.sub.1 -C.sub.4 acyl PA1 (c) --(CH.sub.2).sub.x OCH.sub.2 R.sup.7 wherein R.sup.7 and x are as defined above, PA1 (d) --CHO PA1 (e) --CN, PA1 (f) --COOR.sup.9 wherein R.sup.9 is hydrogen, C.sub.1 -C.sub.4 alkyl or benzyl; PA1 (a) R.sup.14 -(CH.sub.2).sub.x - wherein x and R.sup.14 are, independently, as defined above, PA1 (b) R.sup.14 R.sup.13 CH(CH.sub.2).sub.y - wherein y is zero, one, two, three, four or five, R.sup.14 is as defined above, and R.sup.13 is lower alkyl, cycloalkyl, naphthyl, phenyl unsubstituted or substituted with from one through five substituents, preferably from one through three substituents, comprising alkyl, halo, trifluoromethyl, amino, N-lower monoalkyl amino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, or nitro; PA1 (c) --COR.sup.5 wherein R.sup.5 is
(a) R.sup.14 --(CH.sub.2).sub.x -- wherein x and R.sup.14 are, independently, as defined above, PA2 (b) R.sup.14 R.sup.13 CH(CH.sub.2).sub.y -- wherein y is zero, one, two, three, four or five, R.sup.14 is as defined above, and R.sup.13 is lower alkyl, cycloalkyl, naphthyl, phenyl unsubstituted or substituted with from one through five substituents, comprising alkyl, halo, tri-fluoromethyl, amino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, or nitro; PA2 (c) --COR.sup.5 wherein R.sup.5 is PA2 (i) alkyl of from one to fifteen carbons, inclusive, PA2 (ii) ##STR4## wherein R.sup.14 and y are, independently, as defined above, and R.sup.15 is H, lower alkyl, cycloalkyl, naphthyl, phenyl unsubstituted or substituted with from one through five substituents, preferably from one through three substituents, comprising alkyl, halo, trifluoromethyl, amino, N-lower monoalkylamino, N,N-lower dialkylamino, lower thioalkyl, lower alkylsulfonyl, OH, C.sub.1 -C.sub.4 alkoxy, or nitro, PA2 (iii) --(CH=CR.sup.12)-R.sup.16, wherein R.sup.12 is hydrogen or lower alkyl and R.sup.16 is PA2 (iv) R.sup.14 (CH.sub.2).sub.y R.sup.12 N- wherein y, R.sup.14 and R.sup.12 are, independently, as defined above, PA2 (v) R.sup.14 -(CH.sub.2).sub.y -0- wherein y and R.sup.14 are independently as defined above, PA2 (vi) ##STR6## wherein R.sup.14, R.sup.15, and y are independently as defined above, (d) --SO.sub.2 R.sup.5 wherein R.sup.5 is, independently, as defined above, preferably R.sup.14 -(CH.sub.2).sub.y -wherein R.sup.14 and y are, independently, as defined above;
(i) alkyl of from one to fifteen carbons, inclusive, PA3 (ii) ##STR1## wherein R.sup.14 and y are, independently, as defined above, and R.sup.15 is H, lower alkyl, cycloalkyl, naphthyl, phenyl previously learned tasks and to ameliorate, at least in part, an anticholinergic effect on performance (European Patent application EP 288,907 to Squibb, published Nov. 2, 1988). PA3 (a) alkyl of from four to twenty carbons, inclusive, PA3 (b) ##STR5## wherein y, R.sup.14 and R.sup.15 are, independently, as defined above, and
Evidence for a role of AII in cholinergic function was also reported by Barnes et al. (Brain Research 491: 136-143 (1989), who examined the effect of AII in an in vitro model of potassium stimulated release of [.sup.3 H]ACh. AII, but not AI, reduced potassium-stimulated release of ACh without effects on basal levels. This effect was antagonized by the AII antagonist [1-sarcosine, 8-threonine]angiotensin II. These results suggest that AII can inhibit the release of ACh in the entorhinal cortex of rat brain.
The results summarized above suggest that increased AII activity in the brain may exert an inhibitory effect on cholinergic neurons, resulting in impaired cognitive performance. Thus, compounds that block AII receptor activation may enhance cognitive performance.
Carini and Duncia, U.S.S.N. 050,341, filed May 22, 1987, which is a continuation-in-part of U.S.S.N. 884,920, filed July 11, 1986, disclose angiotensin II receptor blocking imidazoles (also EP 0253 310, published 20.01.88, and EP 0324 377, published July 19, 1989).
Blankley et al., U.S. Pat. No. 4,812,462, issued Mar. 14, 1989, to Warner-Lambert, disclose 4,5,6,7-tetrahydroimidazo-[4,5-c]-pyridine derivatives, which are said to be useful for the treatment of hypertension.